The
n e w e ng l a n d j o u r na l
transcranial Doppler flow rates were normalized, stopping transfusions led to reversion of high flow and recurrence of stroke.6 Since the incidence of cerebrovascular disease increases throughout life, it seems unlikely that a relatively brief period of transfusion will afford longterm protection of the brain. Are there other approaches to reducing the burden of cerebrovascular disease in persons with sickle cell anemia? A single approved drug, hydroxyurea, is available for treating sickle cell anemia. By inducing increased levels of fetal hemoglobin, hydroxyurea inhibits the tendency of hemoglobin S to form a polymer, thereby protecting the erythrocyte. It might also have other beneficial properties. Hydroxyurea reduces the morbidity and mortality associated with the disease in adults.7,8 In children, its hematologic effects are similar, but the long-term risks and benefits are unknown.9 When hydroxyurea is started in later childhood or in adulthood, it is unlikely to prevent stroke. Will beginning this treatment very early in life maintain sufficiently high fetal hemoglobin levels in enough sickle cells to retard vascular disease?10 Epidemiologic studies suggest that stroke is less affected by fetal hemoglobin than are many other disease complications. Perhaps treatments that interfere with red-cell–endothelium interactions and blunt the abnormal inflammatory process that contributes to the pathophysiology of disease will be useful adjuncts to fetal hemoglobin induction and will further retard the advance of vascular disease. Screening and long-term transfusion are not options in the parts of the world in which sickle cell anemia is most common, making drug treatment a more feasible approach. DeBaun et al. showed that in the short term, screening and transfusion therapy decreased the
of
m e dic i n e
advance of cerebrovascular disease associated with sickle cell anemia. Additional research is required to see whether these results can be effectively translated to medical practice, whether the benefits can be sustained over time, and whether the intended goal of preserving cognitive function without the problems of iron overload is achievable. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Departments of Medicine, Pediatrics, and Pathology and Laboratory Medicine, Boston University School of Medicine, Boston. 1. DeBaun MR, Gordon M, McKinstry RC, et al. Controlled
trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014;371:699-710. 2. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11. 3. Vichinsky EP, Neumayr LD, Gold JI, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 2010;303:1823-31. 4. Chou ST, Jackson T, Vege S, Smith-Whitley K, Friedman DF, Westhoff CM. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood 2013;122:1062-71. 5. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012;120:528-37. 6. Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769-78. 7. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22. 8. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxy urea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003;289:1645-51. [Erratum, JAMA 2003;290:756.] 9. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663-72. 10. Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014;123:481-5. DOI: 10.1056/NEJMe1405776 Copyright © 2014 Massachusetts Medical Society.
Progress in the Prevention and Treatment of RSV Infection Peter F. Wright, M.D. At long last, gratifying progress is evident on many fronts in combating respiratory syncytial virus (RSV) infection. RSV was discovered in 1956 as an agent causing coryza in chimpanzees.1 Its clinical effects became evident shortly thereafter through a strong epidemiologic association of RSV infection with bronchiolitis and pneumonia in young infants.2 In the almost 60 years since the virus was identified, the high776
lights of RSV research have been relatively few, in spite of dedicated groups working in this field. The reasons for this include the difficulty of working with RSV in the laboratory; the confinement of RSV replication in humans to the superficial epithelial cells lining the respiratory tract; the early recognition of the complex immune responses to RSV, in which efforts at prevention of illness led to enhancement of disease
n engl j med 371;8 nejm.org august 21, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY MASS MEDICAL SCHOOL on August 21, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorials
on later natural exposure and repeated infections3; and the difficulty of targeting disease prevention to infants in the first months of life. Why should there be optimism now? Molecular approaches through reverse genetics have allowed a targeted approach to understanding the pathogenesis of RSV infection and an engineered approach to attenuation of the virus.4 Definition at the structural level of RSV epitopes has disclosed new, potential targets for antibody recognition on the fusion (F) protein.5 Vaccine research that had been almost dormant for many decades is awakening from hibernation, with new strategies for disease prevention in infancy (including maternal immunization) being explored. The major global effects of RSV infection have been defined, making it a target for the prevention of childhood respiratory disease on a par with the leading bacterial causes of pneumonia.6 The report by DeVincenzo et al.7 in this issue of the Journal of an active RSV antiviral compound generates a level of enthusiasm similar to that for these other advances. The authors report exciting preliminary data on the effectiveness of a fusion inhibitor, GS-5806, in modulating experimental RSV infection in adults. Many years ago, clues arose that fusion was a critical step in RSV growth in humans during the evaluation of a nonsyncytial mutant of RSV, ts-2, as a potential live-vaccine candidate. This virus grew well in tissue culture, with only limited temperature sensitivity as a marker of possible attenuation. In tissue culture, it formed a nonsyncytial plaque, which indicated that the virus had no fusogenic potential. When ts-2 was evaluated in animal models and then in humans, it unexpectedly proved to be poorly infectious.8 Strengths of the current study of GS-5806 include a human model of RSV disease in which a consistent infection and mild but discernible symptoms are observed, the striking effects of GS-5086 in terms of limiting virus recovery and reducing symptom scores, and the absence of severe treatment-related adverse events in the small number of participants followed to date. Finally, treatment with GS-5806 was started after infection had become established, so there is hope that when the drug is started after the onset of symptoms, it might still have an effect. Because the evaluation of GS-5806 is at an early stage, there are unanswered questions to consider that will influence the further development, usefulness, and uptake of the drug. A partial list
would be the design and end point of an efficacy trial, the choice of dose and duration of therapy, safety and pharmacokinetics in young children, the implications of the development of resistance, ease of manufacture, and cost. Most important is whether GS-5806 or related compounds will have clinical effects with limited or manageable side effects in the most likely candidates for its use: very sick infants or young children, immunosuppressed persons in whom RSV can cause a persistent and severe infection, and elderly persons with underlying cardiopulmonary disease. The fusion of a viral coat protein with cell membranes is a critical step in viral entry for all enveloped viruses, including RSV.9 The licensure of an antiviral drug based on fusion inhibition has been accomplished for human immunodeficiency virus by enfuvirtide.10 The current study lends further weight to the concept that fusion of the host cell membranes with viral surface proteins is a potential target for additional antiviral compounds for enveloped viruses. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, NH. 1. Blount RE Jr, Morris JA, Savage RE. Recovery of cytopatho-
genic agent from chimpanzees with coryza. Proc Soc Exp Biol Med 1956;92:544-9. 2. Chanock RM, Kim HW, Vargosko AJ, et al. Respiratory syncytial virus. I. Virus recovery and other observations during 1960 outbreak of bronchiolitis, pneumonia, and minor respiratory diseases in children. JAMA 1961;176:647-53. 3. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969;89:405-21. 4. Collins PL, Fearns R, Graham BS. Respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease. Curr Top Microbiol Immunol 2013;372:3-38. 5. McLellan JS, Chen M, Joyce MG, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 2013;342:592-8. [Erratum, Science 2013;342:931.] 6. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375:1545-55. 7. DeVincenzo JP, Whitley RJ, Mackman RL, et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 2014;371:711-22. 8. Wright PF, Belshe RB, Kim HW, Van Voris LP, Chanock RM. Administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children. Infect Immun 1982;37:397400. 9. Jardetzky TS, Lamb RA. Activation of paramyxovirus membrane fusion and virus entry. Curr Opin Virol 2014;5:24-33. 10. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998;4:1302-7. DOI: 10.1056/NEJMe1407467 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;8 nejm.org august 21, 2014
777
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY MASS MEDICAL SCHOOL on August 21, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
transcranial Doppler flow rates were normalized, stopping transfusions led to reversion of high flow and recurrence of stroke.6 Since the incidence of cerebrovascular disease increases throughout life, it seems unlikely that a relatively brief period of transfusion will afford longterm protection of the brain. Are there other approaches to reducing the burden of cerebrovascular disease in persons with sickle cell anemia? A single approved drug, hydroxyurea, is available for treating sickle cell anemia. By inducing increased levels of fetal hemoglobin, hydroxyurea inhibits the tendency of hemoglobin S to form a polymer, thereby protecting the erythrocyte. It might also have other beneficial properties. Hydroxyurea reduces the morbidity and mortality associated with the disease in adults.7,8 In children, its hematologic effects are similar, but the long-term risks and benefits are unknown.9 When hydroxyurea is started in later childhood or in adulthood, it is unlikely to prevent stroke. Will beginning this treatment very early in life maintain sufficiently high fetal hemoglobin levels in enough sickle cells to retard vascular disease?10 Epidemiologic studies suggest that stroke is less affected by fetal hemoglobin than are many other disease complications. Perhaps treatments that interfere with red-cell–endothelium interactions and blunt the abnormal inflammatory process that contributes to the pathophysiology of disease will be useful adjuncts to fetal hemoglobin induction and will further retard the advance of vascular disease. Screening and long-term transfusion are not options in the parts of the world in which sickle cell anemia is most common, making drug treatment a more feasible approach. DeBaun et al. showed that in the short term, screening and transfusion therapy decreased the
of
m e dic i n e
advance of cerebrovascular disease associated with sickle cell anemia. Additional research is required to see whether these results can be effectively translated to medical practice, whether the benefits can be sustained over time, and whether the intended goal of preserving cognitive function without the problems of iron overload is achievable. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Departments of Medicine, Pediatrics, and Pathology and Laboratory Medicine, Boston University School of Medicine, Boston. 1. DeBaun MR, Gordon M, McKinstry RC, et al. Controlled
trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014;371:699-710. 2. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11. 3. Vichinsky EP, Neumayr LD, Gold JI, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 2010;303:1823-31. 4. Chou ST, Jackson T, Vege S, Smith-Whitley K, Friedman DF, Westhoff CM. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood 2013;122:1062-71. 5. Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012;120:528-37. 6. Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769-78. 7. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22. 8. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxy urea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003;289:1645-51. [Erratum, JAMA 2003;290:756.] 9. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663-72. 10. Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014;123:481-5. DOI: 10.1056/NEJMe1405776 Copyright © 2014 Massachusetts Medical Society.
Progress in the Prevention and Treatment of RSV Infection Peter F. Wright, M.D. At long last, gratifying progress is evident on many fronts in combating respiratory syncytial virus (RSV) infection. RSV was discovered in 1956 as an agent causing coryza in chimpanzees.1 Its clinical effects became evident shortly thereafter through a strong epidemiologic association of RSV infection with bronchiolitis and pneumonia in young infants.2 In the almost 60 years since the virus was identified, the high776
lights of RSV research have been relatively few, in spite of dedicated groups working in this field. The reasons for this include the difficulty of working with RSV in the laboratory; the confinement of RSV replication in humans to the superficial epithelial cells lining the respiratory tract; the early recognition of the complex immune responses to RSV, in which efforts at prevention of illness led to enhancement of disease
n engl j med 371;8 nejm.org august 21, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY MASS MEDICAL SCHOOL on August 21, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorials
on later natural exposure and repeated infections3; and the difficulty of targeting disease prevention to infants in the first months of life. Why should there be optimism now? Molecular approaches through reverse genetics have allowed a targeted approach to understanding the pathogenesis of RSV infection and an engineered approach to attenuation of the virus.4 Definition at the structural level of RSV epitopes has disclosed new, potential targets for antibody recognition on the fusion (F) protein.5 Vaccine research that had been almost dormant for many decades is awakening from hibernation, with new strategies for disease prevention in infancy (including maternal immunization) being explored. The major global effects of RSV infection have been defined, making it a target for the prevention of childhood respiratory disease on a par with the leading bacterial causes of pneumonia.6 The report by DeVincenzo et al.7 in this issue of the Journal of an active RSV antiviral compound generates a level of enthusiasm similar to that for these other advances. The authors report exciting preliminary data on the effectiveness of a fusion inhibitor, GS-5806, in modulating experimental RSV infection in adults. Many years ago, clues arose that fusion was a critical step in RSV growth in humans during the evaluation of a nonsyncytial mutant of RSV, ts-2, as a potential live-vaccine candidate. This virus grew well in tissue culture, with only limited temperature sensitivity as a marker of possible attenuation. In tissue culture, it formed a nonsyncytial plaque, which indicated that the virus had no fusogenic potential. When ts-2 was evaluated in animal models and then in humans, it unexpectedly proved to be poorly infectious.8 Strengths of the current study of GS-5806 include a human model of RSV disease in which a consistent infection and mild but discernible symptoms are observed, the striking effects of GS-5086 in terms of limiting virus recovery and reducing symptom scores, and the absence of severe treatment-related adverse events in the small number of participants followed to date. Finally, treatment with GS-5806 was started after infection had become established, so there is hope that when the drug is started after the onset of symptoms, it might still have an effect. Because the evaluation of GS-5806 is at an early stage, there are unanswered questions to consider that will influence the further development, usefulness, and uptake of the drug. A partial list
would be the design and end point of an efficacy trial, the choice of dose and duration of therapy, safety and pharmacokinetics in young children, the implications of the development of resistance, ease of manufacture, and cost. Most important is whether GS-5806 or related compounds will have clinical effects with limited or manageable side effects in the most likely candidates for its use: very sick infants or young children, immunosuppressed persons in whom RSV can cause a persistent and severe infection, and elderly persons with underlying cardiopulmonary disease. The fusion of a viral coat protein with cell membranes is a critical step in viral entry for all enveloped viruses, including RSV.9 The licensure of an antiviral drug based on fusion inhibition has been accomplished for human immunodeficiency virus by enfuvirtide.10 The current study lends further weight to the concept that fusion of the host cell membranes with viral surface proteins is a potential target for additional antiviral compounds for enveloped viruses. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, NH. 1. Blount RE Jr, Morris JA, Savage RE. Recovery of cytopatho-
genic agent from chimpanzees with coryza. Proc Soc Exp Biol Med 1956;92:544-9. 2. Chanock RM, Kim HW, Vargosko AJ, et al. Respiratory syncytial virus. I. Virus recovery and other observations during 1960 outbreak of bronchiolitis, pneumonia, and minor respiratory diseases in children. JAMA 1961;176:647-53. 3. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969;89:405-21. 4. Collins PL, Fearns R, Graham BS. Respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease. Curr Top Microbiol Immunol 2013;372:3-38. 5. McLellan JS, Chen M, Joyce MG, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 2013;342:592-8. [Erratum, Science 2013;342:931.] 6. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375:1545-55. 7. DeVincenzo JP, Whitley RJ, Mackman RL, et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 2014;371:711-22. 8. Wright PF, Belshe RB, Kim HW, Van Voris LP, Chanock RM. Administration of a highly attenuated, live respiratory syncytial virus vaccine to adults and children. Infect Immun 1982;37:397400. 9. Jardetzky TS, Lamb RA. Activation of paramyxovirus membrane fusion and virus entry. Curr Opin Virol 2014;5:24-33. 10. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998;4:1302-7. DOI: 10.1056/NEJMe1407467 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;8 nejm.org august 21, 2014
777
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY MASS MEDICAL SCHOOL on August 21, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
